EP0632805B1 - Derives de la melamine utilises dans le traitement du cancer - Google Patents

Derives de la melamine utilises dans le traitement du cancer Download PDF

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Publication number
EP0632805B1
EP0632805B1 EP93907928A EP93907928A EP0632805B1 EP 0632805 B1 EP0632805 B1 EP 0632805B1 EP 93907928 A EP93907928 A EP 93907928A EP 93907928 A EP93907928 A EP 93907928A EP 0632805 B1 EP0632805 B1 EP 0632805B1
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Prior art keywords
compound
formula
treatment
trimelamol
hydroxymethyl
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EP93907928A
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German (de)
English (en)
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EP0632805A1 (fr
Inventor
Michael The Institute Of Cancer Research Jarman
Helen Mary The Institute Of Cancer Research Coley
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Cancer Research Campaign Technology Ltd
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Cancer Research Campaign Technology Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • C07D251/70—Other substituted melamines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to novel 2,4,6-triamino-1,3,5-triazines, compositions containing them, processes for making them and their use in the treatment of carcinomas, particularly ovarian carcinomas.
  • Trimelamol 2,4,6-tris ⁇ (hydroxymethyl) (methyl) amino)-1,3,5-triazine
  • Trimelamol is clinically active, particularly against ovarian carcinomas, but its clinical development has been halted due to difficulties with formulation due to instability with respect to the formation of dimers during formulation. It has been established that the half-life of trimelamol activity in humans is short and that may limit its clinical efficacy (I.R. Judson, et al Cancer Res. 49, 5475-5479, 1989). We believe that this is, in part, due to the chemical instability of the N-hydroxymethyl functions resulting in the release of formaldehyde.
  • this invention provides novel 2,4,6-triamino-1,3,5-triazines having the following general formula: wherein each R 1 which may be the same or different, is C 1-4 alkyl, 2,2,2-trifluoroethyl or propargyl and R 2 is hydrogen. It is preferred that all three R 1 groups, when alkyl, are all methyl.
  • the organic groups -CH 2 CF 3 and -CH 2 C ⁇ CH are electron-withdrawing. Because of the greater stability conferred on such compounds by the presence of such electron withdrawing substituents, which may constitute in lengthening the half-life and also in improving amenability to formulation, they may be prepared by allowing tris-hydroxymethyl compounds or precursors thereof to decompose in aqueous organic media and separating from the mixture of products (see Fig. 1) thus generated the appropriate compounds of the present invention, for example by chromatography on silica gel.
  • trimelamol have a similar level of activity against carcinomas, particularly ovarian carcinomas, as trimelamol, but are more stable and do not form dimers and polymers and thus are more amenable to formulation.
  • the intermediates are prepared by reacting a cyanuric halide of general formula: wherein X is fluoro or chloro with an amine of the formula R 1 -NH 2 or R 1 R 2 NH 2 , wherein R 1 and R 2 are as defined in formula (I), optionally in the presence of caesium fluoride.
  • the presence of these compounds does not significantly affect the activity of the preparation of the compound of the invention in biological assays.
  • the purity of the preparation may be increased by recrystallisation.
  • the material may be dissolved in methanol-water (eg at a ratio of 9:1), and recrystallised.
  • the compounds of this invention are biologically active and are of use against ovarian carcinomas, particularly against cisplatin-resistant ovarian carcinomas.
  • compositions which comprise, as active ingredient, at least one compound of general formula I, in association with a pharmaceutically acceptable carrier or diluent.
  • the compounds of the invention will normally be administered orally or by injection.
  • compositions for parenteral administration will normally be solutions in aqueous saline, which is pyrogen free for human use. Such compositions can be administered intravenously or intraperitoneally.
  • compositions for oral administration will mostly be in solid or liquid form, mostly as tablets, capsules, lozenges, etc.
  • Liquid compositions can be solutions or dispersions in aqueous or non-aqueous media. Ideal solutions are of neutral or alkaline pH and of low ionic strength e.g. 5% dextrose.
  • Suitable daily doses of the compounds of the invention in therapeutic treatment of the human or animal body range from about 100mg to 3g/m 2 body-surface.
  • T 1/2 measurements were made by measurement of the disappearance of compound by decreasing peak area with time, using a Data System 450MT2 data acquisition system (Kontron Instruments, Watford, UK) linked directly to the detector on the HPLC system (set at 225 nM). T 1/2 measurements were read from a semi-logarithmic plot of peak area (y) versus time (x).
  • the cytotoxicity of CB7646 and CB7683 was compared with trimelamol against mammalian tumour cell lines using the MTT assay.
  • This assay is based upon the selective ability of living but not dead cells to reduce the tetrazolium salt MTT (3-[4,5-dimethylthiazol-2-yl]-25-diphenyl tetrazolium bromide) to purple formazan (Mosmann et al, 1983, J. Immun. Methods 65; 55-63; Carmichael et al (1987) Cancer Res. 47; 936-942).
  • Cell lines were grown in culture with continual drug exposure.
  • the IC 50 values (in ⁇ m) of the compounds i.e.
  • CB 7646 prepared in accordance with Example 1 against ADJ/PC6 tumour in mice were compared with that of trimelamol.
  • animals bearing tumours of comparative size were placed into groups of 4 and treated with drug on 5 consecutive days, and then left until day 30.
  • Tumours from the treated and controls were dissected and weighed as a measure of tumour growth.
  • Compounds were given in 5% DMSO/dextrose.
  • Example 6 was repeated to obtain more precise LD 50 values.
  • the LD 50 , ED 90 and T.I. values were calculated and shown in Table 4.
  • CB7646 was tested in vivo against ovarian cancer xenografts of the PXN65 cell line transplanted into mice, substantially in accordance with Harrap et al, Annals of Oncology, 1990, 1;65-76.
  • PXN65 is a cisplatin-sensitive line.
  • Mice treated with either trimelamol or CB7646 showed tumour regression within 28 days whereas in untreated controls tumour growth was uncontrolled, leading to death.
  • the results are summarised in Table 5.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Claims (10)

  1. Composé de formule générale :
    Figure 00180001
    dans laquelle chaque R1, qui peuvent être identiques ou différents, est un groupe alkyle en C1-C4, 2,2,2-trifluoroéthyle ou propargyle, et R2 est un hydrogène.
  2. 2,4-Bis[(hydroxyméthyl)(méthyl)amino]-6-méthylamino-1,3,5-triazine.
  3. Une composition pharmaceutique comprenant un ingrédient actif qui est un composé tel que défini dans la revendication 1 ou 2, avec un diluant ou véhicule inerte.
  4. Composé selon la revendication 1 ou 2, ou composition pharmaceutique selon la revendication 3, pour l'utilisation dans une méthode de traitement du corps humain ou animal par une thérapie effectuée sur le corps humain ou animal.
  5. Composé ou composition pour l'utilisation selon la revendication 4 pour le traitement d'un cancer ovarien.
  6. Un procédé de préparation d'un composé de formule I :
    Figure 00180002
    dans laquelle chaque R1 est un groupe alkyle en C1-C4, R2 est un hydrogène, qui comprend la réaction d'un composé de formule II
    Figure 00190001
    dans laquelle R1 est tel que défini dans la formule I, avec du formaldéhyde, facultativement en présence de carbonate de potassium.
  7. Procédé selon la revendication 6, dans lequel le formaldéhyde est utilisé à une concentration allant de 2 à 5 % (p/v).
  8. Procédé selon la revendication 6 ou 7, qui comprend en outre une étape de recristallisation.
  9. Un procédé de préparation d'un composé bis-hydroxyméthylé de formule I tel que défini dans la revendication 1, qui comprend (a) la décomposition du dérivé trishydroxyméthylé correspondant, de formule :
    Figure 00190002
    dans laquelle R1 est tel que défini dans la revendication 1, dans des conditions permettant d'obtenir le composé de formule I, et (b) la récupération du composé de formule I.
  10. Utilisation d'un composé tel que défini dans la revendication 1 ou 2, pour la fabrication d'un médicament pour le traitement de cancer.
EP93907928A 1992-03-27 1993-03-26 Derives de la melamine utilises dans le traitement du cancer Expired - Lifetime EP0632805B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9206768 1992-03-27
GB929206768A GB9206768D0 (en) 1992-03-27 1992-03-27 New compounds for use in the treatment of cancer
PCT/GB1993/000625 WO1993020056A1 (fr) 1992-03-27 1993-03-26 Derives de la melamine utilises dans le traitement du cancer

Publications (2)

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EP0632805A1 EP0632805A1 (fr) 1995-01-11
EP0632805B1 true EP0632805B1 (fr) 1998-07-08

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US (2) US5534625A (fr)
EP (1) EP0632805B1 (fr)
JP (1) JPH07505380A (fr)
AT (1) ATE168105T1 (fr)
AU (1) AU676677B2 (fr)
DE (1) DE69319590T2 (fr)
DK (1) DK0632805T3 (fr)
ES (1) ES2118945T3 (fr)
GB (1) GB9206768D0 (fr)
WO (1) WO1993020056A1 (fr)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0787424B2 (ja) * 1993-06-30 1995-09-20 日本電気株式会社 バースト信号送信システム
WO1997024338A1 (fr) * 1995-12-27 1997-07-10 Nissan Chemical Industries, Ltd. Methodes de modification de derives de 1,3,5-triazine
US6335339B1 (en) 1998-01-13 2002-01-01 Scriptgen Pharmaceuticals, Inc. Triazine antiviral compounds
EP1053230A1 (fr) * 1998-01-13 2000-11-22 Scriptgen Pharmaceuticals, Inc. Composes de triazine antiviraux
US6262053B1 (en) * 1999-06-23 2001-07-17 Parker Hughes Institute Melamine derivatives as potent anti-cancer agents
CN1402722A (zh) * 1999-11-29 2003-03-12 阿文蒂斯药物股份有限公司 芳胺衍生物及其作为抗端粒酶剂的用途
US6645964B1 (en) * 1999-11-29 2003-11-11 Aventis Pharma S.A. Chemical derivatives and their application as antitelomerase agent
FR2801588B1 (fr) * 1999-11-29 2002-03-01 Aventis Pharma Sa Derives chimiques et leur application comme agent antitelomerase
FR2819255B1 (fr) * 2001-01-09 2003-02-28 Aventis Pharma Sa Derives chimiques et leur application comme agent antitelomerase
US6858608B2 (en) 2001-01-09 2005-02-22 Aventis Pharma S.A. Chemical derivatives and their application as antitelomerase agents
US6887873B2 (en) * 2001-03-23 2005-05-03 Aventis Pharma S.A. Triazine derivatives and their application as antitelomerase agents
FR2822468B1 (fr) * 2001-03-23 2008-06-20 Aventis Pharma Sa Derives chimiques et leur application comme agent anti-telomerase
CO5380035A1 (es) * 2001-03-23 2004-03-31 Aventis Pharma Sa Derivados quimicos y su aplicacion como agente antitelomerasa
US20070232572A1 (en) * 2003-02-07 2007-10-04 Aventis Pharma S.A. Chemical derivatives as antitelomerase agents which bind specifically to the G-quadruplex DNA structures and their application as a specific anticancer agent
CN101684115B (zh) * 2008-09-26 2011-12-21 上海医药工业研究院 4-(5-((2-(4-吗啉基-6-苯氨基-1,3,5-三嗪-2-基)亚肼基)甲基)呋喃-2-基)苯甲酸、其制备方法及用途

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2476548A (en) * 1949-07-19 Preparation of triazinfliufitmlts
US2566225A (en) * 1951-08-28 Process for preparing substituted
US2420157A (en) * 1943-02-12 1947-05-06 American Cyanamid Co Resin finishing of textiles
US2485059A (en) * 1944-05-06 1949-10-18 Monsanto Chemicals Melamine condensation product
US2476127A (en) * 1946-06-07 1949-07-12 American Cyanamid Co Reaction product of a polymethylol melamine and an aromatic amine
US2565194A (en) * 1947-03-27 1951-08-21 American Cyanamid Co Chlorotriazine resins and process of making the same
US2537131A (en) * 1947-07-18 1951-01-09 American Cyanamid Co Continuous process for the preparation of alkylated alkylol melamine
US2520619A (en) * 1948-10-05 1950-08-29 American Cyanamid Co Preparation of triethylenemelamine
US2709693A (en) * 1950-12-04 1955-05-31 Ciba Ltd Etherified condensation products of formaldehyde with amino-1:3:5-triazines containing at least two aminogroups
US2781553A (en) * 1953-03-13 1957-02-19 American Cyanamid Co Spray molding process
GB9106170D0 (en) * 1991-03-22 1991-05-08 Jarman Michael New compounds for use in the treatment of cancer

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DE69319590D1 (de) 1998-08-13
ES2118945T3 (es) 1998-10-01
AU676677B2 (en) 1997-03-20
DE69319590T2 (de) 1998-11-12
DK0632805T3 (da) 1999-04-19
ATE168105T1 (de) 1998-07-15
WO1993020056A1 (fr) 1993-10-14
EP0632805A1 (fr) 1995-01-11
AU3894293A (en) 1993-11-08
JPH07505380A (ja) 1995-06-15
GB9206768D0 (en) 1992-05-13
US5854244A (en) 1998-12-29
US5534625A (en) 1996-07-09

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